JP2018531268A - Aqueous composition containing dantrolene - Google Patents

Abstract

The present invention relates to an aqueous composition comprising dantrolene or any of its pharmaceutically acceptable salts and a cyclodextrin derivative, wherein the pH of the aqueous composition is greater than 7. Furthermore, this invention relates to the kit containing the powder obtained by drying the composition of this invention, and the powder of this invention.

Description

  The present invention relates to an aqueous composition comprising dantrolene or a pharmaceutically acceptable salt thereof and a cyclodextrin derivative, wherein the pH of the aqueous composition is greater than 7. Furthermore, this invention relates to the kit containing the powder obtained by drying the composition of this invention, and the said powder.

  Malignant hyperthermia is a life-threatening genetic susceptibility to volatile anesthetics and depolarizing neuromuscular blockers used for general anesthesia. In sensitive individuals, these drugs supply oxygen, remove carbon dioxide, overwhelm the body's ability to regulate body temperature, and play a skeletal oxidative metabolism that leads to circulatory collapse and death if not treated quickly. May induce targeted and uncontrolled increases.

  The currently selected treatment for malignant hyperthermia is the administration of dantrolene, a hydantoin derivative first described in 1967. Dantrolene is a post-synaptic muscle relaxant that reduces excitatory contraction coupling in muscle cells. However, dantrolene is sparingly soluble in water, resulting in a formulation that exhibits many undesirable properties. These problems include cumbersome and sometimes inaccurate preparations, considerable time investment and use of high temperatures in the preparation of solutions suitable for intravenous administration, and effective doses (typically 2.5-10 mg / Included is the need to administer large volumes of solution to deliver (kg body weight range). The low solubility in water extends to the pharmaceutically acceptable salt of dantrolene that precipitates in solution over time in the form of the free acid. The resulting mixture is unacceptable for injection. The short shelf life of the solution has been addressed in the art by keeping the powder obtained by lyophilizing the dantrolene solution at hand. However, final administration of the formulation generally involves reconstitution of this powder into an injectable liquid, preferably involving dissolving the powder in an aqueous diluent. Accordingly, there is a need to provide a storage-stable and parenterally injectable formulation of dantrolene and its salts that exhibit increased solubility in preferred aqueous preparations, and an injectable solution that allows effective administration of an effective amount of dantrolene. Still exists.

  EP 2583670 provides a method for producing a low-solubility pharmaceutical, particularly a dantrolene sodium formulation for intravenous use, using a tert-butyl alcohol (TBA) cosolvent system in the formulation.

  US 2014/00099382 provides a small formulation of dantrolene, safe for injection, comprising dantrolene sodium, water-soluble polysorbate, sorbitol or mannitol, and water as a liquid carrier, dantrolene sodium and water containing dantrolene sodium particles in water Both exist as colloidal dispersions.

  US 6,407,079 relates to pharmaceutical compositions comprising inclusion compounds of poorly water-soluble or water-labile drugs with β-cyclodextrin ethers or β-cyclodextrin esters and methods for their preparation.

  WO 99/62958 relates to cyclodextrin derivatives having at least one lower alkyl group and at least one C2-20 alkanoyl group in the molecule and is suitable for intimate mixing of pharmaceutical products.

  Cyclodextrins can be used to increase drug solubility, stability and bioavailability. Although generally known for their stabilizing effects, cyclodextrins can impart destabilizing effects to drugs through direct catalysis. Catalysis is related to the deprotonation of the hydroxyl group located at the edge of the cyclodextrin cavity. This catalytic effect is mainly observed under basic conditions and increases with increasing pH (A. Raheed et al, Cyclodextrins as Drug Carrier Molecule: A Review, Scientia Pharmaceuticals 2008, 76, 567-598).

  Furthermore, dantrolene is known to undergo hydrolysis in an alkaline solution and decompose by hydantoin ring opening to form a ring-opening compound. Degradation is accelerated with increasing pH value and is enhanced at higher temperatures. Studies have shown that certain base catalysts become more pronounced as the pH increases from 7.5 to 9.5, resulting in an increase in the decomposition rate of dantrolene (SR Khan et al, (Stability Characterization, Kinetics and Mechanism of Degradation of Dantrolene in Aqueous Solution: Effect of pH at Temperature, 2, Pharmacology, 2)

  In WO2010 / 126818A1, a composition is disclosed in which excess dantrolene is mixed with a small amount of cyclodextrin derivative to provide a non-uniform paste. Jansen et al: “Some physical-chemical properties of dantrolene and two of analogues”, International Journal of Pharmaceuticals, ElsevierLV, 75. No. 2-3, 20 September 1991 (1991-09-20), pages 193-199, discloses the possibility of mixing dantrolene with cyclodextrin in a molar ratio of 1: 100 to 1: 1000.

  Further techniques include US 6,407,079 B1; and Rashed et al: “Cyclodextrins as Drug Carrier Module: A Review”, Scientific Pharmacia, vol. 76, no. 4,1 January 2008 (2008-01-01), pages 567-598.

  All hospitals face the above problems because all hospitals are encouraged to take dantrolene due to the high impact of malignant hyperthermia. Accordingly, there is a need for a dantrolene solution that is easy to prepare and exhibits acceptable stability over time.

  Accordingly, it is an object of the present invention to provide an aqueous composition comprising dantrolene or a pharmaceutically acceptable salt thereof that exhibits increased storage stability and solubility in an aqueous liquid formulation.

  It is a further object of the present invention to provide a composition, particularly a powder, comprising either dantrolene or a pharmaceutically acceptable salt thereof that can quickly and easily clarify the solution.

  During the development of the present invention, surprisingly, in contrast to the teaching of the prior art, for an aqueous composition comprising either dantrolene or a pharmaceutically acceptable salt and a cyclodextrin derivative at an alkaline pH value, It has been found that increased storage and chemical stability and solubility can be achieved.

FIG. 1 shows the results of solubility measurements at a pH value of 6.0. FIG. 2 shows the results of the solubility measurement at a pH value of 7.0. FIG. 3 shows the results of the solubility measurement at a pH value of 8.0. FIG. 4 shows the results of the solubility measurement at a pH value of 9.0. FIG. 5 shows the results of solubility measurements at a pH value of 10.0. FIG. 6 shows the degradation profile of dantrolene sodium in the test solution for 10 days at a pH value of 6.0. FIG. 7 shows the degradation profile of dantrolene sodium in the test solution for 10 days at a pH value of 7.0. FIG. 8 shows the degradation profile of dantrolene sodium in the test solution for 10 days at a pH value of 8.0. FIG. 9 shows the degradation profile of dantrolene sodium in the test solution for 10 days at a pH value of 9.0. FIG. 10 shows the degradation profile of dantrolene sodium in the test solution at a pH value of 10.0 for 10 days. FIG. 11 shows the correlation between the solubility of dantrolene sodium salt and the pH of the solution. FIG. 12 shows the correlation between the solubility of dantrolene sodium salt and the pH of the solution. The result of having compared the powder of this invention obtained by freeze-drying the solution 2 with the powder of WO2010 / 12681 A1 is shown. The turbidity results of the powder formulation according to the invention and the preparation according to WO 2010/126818 A1 are shown.

One embodiment of the present invention
i) a component selected from one or more members of the group consisting of dantrolene and pharmaceutically acceptable salts of dantrolene (A); and ii) a component selected from one or more members of the group consisting of cyclodextrin derivatives (B)
Wherein the pH of the composition is greater than 7 and the molar ratio of component (A) to component (B) is 1: 2 to 1:30, preferably 1: 3 to 1 : 30.

  The aqueous composition is preferably liquid at 20 ° C.

  Throughout the specification, the values and parameters mentioned are measured at 20 ° C. unless otherwise stated.

Ingredient (A)
Component (A) is an essential component of the aqueous composition of the present invention.
Component (A) is selected from the group consisting of dantrolene and pharmaceutically acceptable salts thereof.
Component (A) can be represented by the following formula (I), where formula (I) represents dantrolene.

The pharmaceutically acceptable salt of dantrolene refers to the deprotonated form of dantrolene and the cation counter ion X ⁺ . The cation counter ion X ⁺ is preferably selected from the group of alkali metals, alkaline earth metals, ammonium, alkylammonium, polyalkylammonium, arylammonium, substituted or unsubstituted quinolizinium and substituted or unsubstituted pyridinium.

The pharmaceutically acceptable salt of dantrolene refers to the salt of dantrolene, where the cationic counterion X ⁺ for the dantrolene anion is preferably sodium, potassium, ammonium, calcium, magnesium, a physiologically acceptable amino acid. Selected from ammonium salts of compounds, in particular arginine, lysine, meglumine, tromethamine; choline, benzyltrimethylammonium, tetramethylammonium, N-methylpyridinium, tetrabutylammonium, 2- (2,3-dihydroxy-1-propylamino ) -Quinolizinium, quinolizinium, 2-carbonyl-1-methylpyridinium, 2,3-dimethyl-1-phenyl-4-trimethylammonium 3-pyrazolin-5-one, dimethylammonium, 1,3- It is selected from methyl imidazolium and 2- (1-hydroxy-2-methyl) group consisting of trimethyl ammonium.

In a preferred embodiment, the counter ion X ⁺ for the dantrolene anion is selected from the group consisting of sodium, potassium, ammonium, calcium and magnesium. In a particularly preferred embodiment, the counter ion X ⁺ for the dantrolene anion is sodium.

  Surprisingly, it has been found that the stability of component (A) in the composition of the present invention can be increased by increasing the pH of the composition. Accordingly, in a preferred embodiment of the composition, the pH is in the range of 7.5 to 10.5, preferably 8.0 to 10.0, more preferably 8.5 to 9.5.

  In a preferred embodiment, component (A) is present in the composition of the invention in an amount of 0.1 to 10 mg / ml, preferably 0.2 to 7.0 mg / ml, especially 0, based on the volume of the aqueous composition. Present in concentrations ranging from 3 to 6.0 mg / ml.

  Containing component (A) at a concentration in the range of 0.25 to 25.0 mmol / l, more preferably 0.50 to 17.50 mmol / l, especially 0.75 mmol / l to 15.0 mmol / l.

Ingredient (B)
A further essential component of the aqueous composition of the present invention is component (B).
Component (B) is selected from the group consisting of cyclodextrins and cyclodextrin derivatives.

  Cyclodextrins are cyclic (α-1,4) linked oligosaccharides having a hydrophobic central cavity and a hydrophilic outer surface. Due to the truncated cone or torus, the cyclodextrin can interact with an appropriately sized molecule to cause the inclusion complex to form. Examples of suitable cyclodextrins are β-cyclodextrin or γ-cyclodextrin.

  Surprisingly, it has been found that the water solubility of component (A) can be increased by the introduction of substituents into component (B). In a preferred embodiment, component (B) is a derivative of cyclodextrin, preferably a derivative of cyclodextrin (preferably β-cyclodextrin), which is preferably preferably alkyl, hydroxyalkyl, carboxyalkyl, It includes one or more substituents selected from alkylcarbonyl, carboxyalkoxyalkyl, sulfoalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl and hydroxyl- (mono or poly) alkyl groups.

  In the above, the terms “alkyl” and “alkylene” should be understood to include both straight and branched hydrocarbon groups which may be substituted or unsubstituted.

  Preferably, each alkyl or alkylene moiety contains up to 6 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, especially 3 or 4 carbon atoms.

Sulfoalkyl preferably means a —C _1-10 -alkyl-SO ₃ H moiety or the corresponding pharmaceutically acceptable salt thereof. Preferred counter ions are those defined as counter ion X ⁺ of component (A) above.

  In a preferred embodiment, component (B) is selected from β-cyclodextrin and β-cyclodextrin derivatives.

  More preferably, the component (B) is β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin, 2-hydroxy. In an embodiment of the invention selected from the group consisting of propyl-γ-cyclodextrin, (2-carboxymethoxy) propyl-β-cyclodextrin, sulfonylbutyl-β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin is there.

  In a preferred embodiment, component (B) is represented by formula (II).

Wherein one or more substituents R is H, alkyl, hydroxyalkyl, carboxyalkyl, alkylcarbonyl, carboxyalkoxyalkyl, —C _1-10 -alkyl-SO ₃ H or a corresponding pharmaceutically acceptable salt thereof. Independently selected from the group consisting of alkylcarbonyloxyalkyl, alkoxycarbonylalkyl and hydroxy- (mono or poly) alkyl.

  Preferably, each alkyl or alkylene moiety contains up to 10 carbon atoms, more preferably 1 to 6 carbon atoms, even more preferably 2 to 4 carbon atoms, especially 3 or 4 carbon atoms. Including.

In a preferred embodiment, one or more of the substituents R is from the group consisting of H, —CH ₂ CH (CH ₃ ) OH, — (CH ₂ ) ₄ SO ₃ Na, —CH ₃ , glucosyl, hydroxyethyl and maltosyl. Selected.

  In a particularly preferred embodiment, component (B) is selected from the group consisting of 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin sodium salt and 2-hydroxyethyl-β-cyclodextrin. In a particularly preferred embodiment, component (B) is 2-hydroxypropyl-β-cyclodextrin.

  Best results are achieved when component (B) is a cyclodextrin having a molar substitution (MS) in the range of 0.05 to 10, preferably β-cyclodextrin. Thus, component (B) is a cyclodextrin having an average molar substitution in the range of 0.05 to 10, preferably 0.2 to 2, in particular 0.25 to 1, in particular 0.5 to 0.8. Embodiments of the invention are preferred. Average molar substitution is generally used as a measure of the average number of moles of all substituents per glucose unit.

  In a particularly preferred embodiment, component (B) is 2-hydroxypropyl-β having a molar substitution of 0.2 to 0.9, preferably 0.3 to 0.8, in particular 0.5 to 0.7. -Cyclodextrin.

  Preferably, the aqueous composition of the present invention comprises component (B) at a concentration ranging from 15 to 400 mg / ml, preferably from 20 to 350 mg / ml, especially from 50 to 300 mg / ml, based on the volume of the aqueous composition. Including.

  In one embodiment of the invention, the aqueous composition comprises component (B) in the range of 10-300 / l, preferably 14-250 mmol / l, especially 36-210 mmol / l, based on the total volume of the aqueous composition. Contain at a concentration of

  In developing the present invention, a careful balance was established between the amount of component (A) and the amount of component (B) in the aqueous composition of the present invention. The best results regarding the stability of component (A) are that the molar amount of component (B) is higher than the molar amount of component (A), and the molar ratio of (A) :( B) is from 1: 2 to 1:30. It is preferably achieved when it is 1: 3 to 1:30.

  Accordingly, embodiments of the present invention in which the molar ratio of component (A) to component (B) is in the range of 1: 5 to 1:18 are more preferred.

  Preferably, the weight ratio of component (A) to component (B) in the composition of the present invention ranges from 1:10 to 1: 100, preferably 1:17 to 1:65. However, in a preferred embodiment, in the case of discrepancies, the molar ratio takes precedence throughout the description of the difference from the molar ratio, ie the molar ratio (or other value) is changed so that the molar ratio is satisfied. There is a need.

  The aqueous composition according to the invention has a pH higher than 7. A pH adjusting agent can be used to adjust the pH value to the desired range and compensate for possible diluent acidity. Accordingly, in a preferred embodiment, the aqueous composition further comprises a pH adjusting agent. The pH adjuster in the sense of the present invention is the pH of the aqueous composition of the present invention within a specific range, for example, more than 7, preferably 7.5 to 10.5, more preferably 8.0 to 10.0, especially Preferably, it is a component or system that can be adjusted and maintained at 8.5 to 9.5.

  In a preferred embodiment, the pH modifier is selected from the group consisting of citrate, carbonate, phosphate, arginine, lysine, meglumine, tromethamine, histidine and mixtures thereof.

  The pH adjuster can be used as a pH buffer or as part of a pH buffer system.

  In a preferred embodiment, the pH adjusting agent is present in the composition of the present invention in an amount suitable to adjust and maintain the pH of the composition within the alkaline range. Preferably, the amount of pH adjusting agent in the composition is selected relative to the amount of component (A) present in the composition of the invention. In a preferred embodiment, the molar ratio of component (A) to pH regulator ranges from 20: 1 to 1:20, preferably from 10: 1 to 1:10, particularly preferably from 8: 1 to 1: 5. .

  The aqueous composition of the present invention comprises an aqueous diluent. Preferably, the diluent is water or a mixture of a physiologically acceptable solvent and water. Usually, the amount of water is higher than 50% by weight, preferably higher than 75% by weight, in particular higher than 95% by weight, based on the total amount of diluent. In one aspect of the invention, the weight ratio of water to organic solvent in the aqueous diluent is at least 1: 2, preferably at least 1: 1, more preferably at least 2: 1, especially at least 5: 1 or at least 10 :. 1, in particular at least 20: 1 or at least 50: 1. In a further embodiment of the invention, the diluent comprises at least 0.5% by weight of organic solvent, preferably at least 1.0% by weight, more preferably at least 5% by weight, in particular 0.5-30% by weight, The amount is based on the total weight of the diluent. Suitable diluents for the aqueous composition are defined below.

  As known to those skilled in the art, the short shelf life of aqueous compositions containing dantrolene compounds is addressed by drying the aqueous composition and storing the resulting powder until reconstitution just prior to use. Has been. However, these powders are generally poorly soluble and require the use of large amounts of solvent to make them suitable for injection. It is a further object of the present invention to provide a formulation of dantrolene salts, such as dantrolene, particularly the sodium salt of dantrolene, which is quickly and reliably reconstituted in emergency clinical situations and in non-emergency and preventive environments. In particular, the formulation is such that a complete therapeutic dose of 300 mg or 200 mg of dantrolene sodium salt can be reconstituted in less than 1 minute by a single clinician in a clinical setting. Surprisingly, it has been found that the powder obtained by drying the composition of the invention is readily soluble in water or a suitable aqueous diluent.

  Accordingly, a further embodiment of the present invention is a powder obtained by drying the aqueous composition of the present invention. The aqueous composition of the present invention can be dried by any suitable means known to those skilled in the art. In a preferred embodiment, the powder of the present invention is obtained by lyophilization of the aqueous composition of the present invention. In a preferred embodiment, the powder of the present invention is an instant powder, ie a powder that dissolves immediately in water. In this context, immediate dissolution should be understood to mean that 100% of the powder dissolves within 30 seconds with stirring at 20 ° C.

  As discussed above, an important step in the treatment of malignant hyperthermia is the immediate administration of dantrolene compounds. Accordingly, the dantrolene compound should be readily available in an administrable form, preferably in a form suitable for injection. In addition, tedious mixing of ingredients should be avoided on the one hand to save time and on the other hand avoid potential risks to both patients and staff that can be caused by mishandling of ingredients. It is.

  A further object of the present invention is a kit that allows a rapid and accurate preparation of the composition of the present invention.

  The kit according to the present invention comprises at least one first section comprising the powder of the present invention and at least one second section comprising an aqueous diluent.

The aqueous diluent is preferably selected from the group consisting of water and a mixture of water and a physiologically acceptable solvent. Physiologically acceptable solvents are preferably C _1-6 alcohols (especially ethanol), polyethylene glycol, propylene glycol, glycerol, dimethylacetamide, dimethylisosorbide, dimethyl sulfoxide, 1-methyl-2-pyrrolidone and 1-ethyl- It is an organic solvent selected from the group consisting of 2-pyrrolidone. The solvent is usually liquid at room temperature (20 ° C.).

  Preferably, the polyethylene glycol is selected from the group of parenterally injectable polyethylene glycols, especially PEG300, PEG400 and PEG600. In the above terms, “PEG” refers to “polyethylene glycol” and the numbers reflect the average relative molecular weight.

  In a preferred embodiment, the polyethylene glycol is selected from polyethylene glycol having an average relative molecular weight of 200 to 700, more preferably 300 to 600, especially 350 to 550.

  Aqueous diluents are sodium, magnesium, calcium, potassium, chloride, lactate, acetate, malate, gluconate, citrate and bicarbonate; and / or glucose, mannitol, sucrose, trehalose, sorbitol Additional compounds such as salts selected from polyols such as

  The kit according to the invention allows the aqueous composition of the invention to be prepared in situ in a form suitable for injection. The amount of the powder of the invention contained in at least one first section and the amount of water of the aqueous diluent contained in the at least one second section is preferably so that the powder of the invention is completely dissolved. Are adapted to each other.

  The first section and the second section are preferably separated from each other, and are preferably physically separated from each other, for example, separated by a wall or foil.

  In a preferred embodiment, the kit according to the invention is in the form of a bag, cartridge, container, vial, syringe or bottle.

  In a preferred embodiment, the kit is in the form of a bag that includes first and second sections separated from each other by, for example, a septum.

  The kit material is preferably chemically inert and does not react with the contents. Even more preferred is a material that additionally protects the contents of the compartment against any form that can lead to degradation of the contents, for example, heat and / or light exposure. Preferably, the material is selected from the group consisting of glass, organic polymers and mixtures thereof. Further preferred is a kit according to the invention, wherein the kit or at least the first and / or at least the second section is made of a material selected from the group consisting of glass, organic polymers and mixtures thereof. Preferred organic polymers are polyethylene and / or polypropylene.

  Preferably, the kit can be sealed to avoid contamination of the contents, for example by bacteria or other microorganisms.

  In a preferred embodiment of the kit, the sections are arranged to prevent unintentional mixing of the contents.

  A further object of the present invention is a process for the preparation of the aqueous composition of the present invention. This method comprises the steps of dissolving components (A) and (B) in an aqueous diluent and adjusting the pH of the solution above 7.

In a preferred embodiment, the method comprises the following steps:
a) Dissolving component (A) and component (B) in an aqueous diluent to give an aqueous solution of component (A) and component (B) of 1: 2 to 1:30, preferably 1: 3 to 1:30 Obtaining a molar ratio;
b) optionally adjusting the pH of the aqueous solution of step a) to above 7, preferably in the range of 7.5 to 10.5;
c) lyophilizing the aqueous solution obtained in step a) or b) to obtain a dry powder;
d) reconstituting the powder of step c) in an aqueous diluent.

  A further object of the invention is a pharmaceutical formulation comprising the composition of the invention or the powder of the invention.

  A further aspect of the invention comprises (i) comprises or consists of the aqueous composition of the invention, or (ii) comprises or consists of the powder of the invention.

  The formulation according to the invention may further comprise other pharmaceutical excipients and / or adjuvants such as crystallization retarders, antioxidants and fats. The total amount of each member of the list consisting of crystallization retarders and antioxidants is usually less than 10% by weight, preferably less than 3% by weight, more preferably less than 1% by weight, in particular 0, based on the total amount of the formulation. .1% by weight, in particular less than 0.01% by weight. The excipient is preferably chosen to allow safe and accurate administration. In a preferred embodiment, the crystallization retarder is polyvinyl pyrrolidone (PVP). PVP having an average molecular weight of 2000 to 11000 is preferred. Povidone K12 having an average molecular weight of about 2500 or povidone K17 having an average molecular weight of about 10,000 is particularly preferred.

  In a preferred embodiment, the formulation of the present invention or the aqueous composition of the present invention further comprises an osmotic agent.

  Preferably, the osmotic agent is an isotonic or isotonic agent, preferably a nonionic isotonic agent.

  In a more preferred embodiment, the osmotic agent is an aliphatic polyhydroxyalkanol having 2 to 10 carbon atoms, preferably mannitol, fructose, glucose, gluconolactone, gluconate, sucrose, lactose, trehalose. , Dextrose, dextran, hydroxyethyl starch, and mixtures thereof.

  Further preferred osmotic agents are selected from the group consisting of glycine gelatin, calcium glucocorglucoheptanoate, potassium chloride, calcium chloride, sodium chloride and mixtures thereof.

  Preferably, the osmotic agent is present in an amount ranging from 0.5 to 10 weight percent, more preferably from 1 to 7 weight percent, even more preferably from 1.5 to 5 weight percent, especially from 2 to 4 weight percent. . The amounts mentioned are based on the total weight of the formulation or aqueous composition.

  The preferred osmotic pressure of the preparation according to the invention is in the range of 250 mOsm / kg to 600 mOsm / kg, more preferably 280 mOsm / kg to 450 mOsm / kg.

In a preferred embodiment, the formulation or aqueous composition of the invention comprises
Component (A) in an amount ranging from 0.75 mmol / l to 15.0 mmol / l;
Component (B) in an amount ranging from 5.0 mmol / l to 250.0 mmol / l;
Aqueous diluent;
Optionally comprising or consisting of a pH regulator in an amount ranging from 0.2 mmol / l to 20.0 mmol / l; and optionally an osmotic agent in an amount ranging from 25.0 mmol / l to 250.0 mmol / l. Where the concentration is based on the total volume of the formulation or aqueous composition and the molar ratio of component (A) to component (B) ranges from 1: 2 to 1:30, preferably from 1: 3 to 1:30. It is.

In a preferred embodiment, the formulation or aqueous composition of the invention is injectable,
Dantrolene sodium salt at a concentration ranging from 1.5 to 15 mg / ml, preferably from 1.6 to 11 mg / ml;
2-hydroxypropyl-β-cyclodextrin at a concentration in the range of 75-350 mg / ml, preferably 80-320 mg / ml;
Aqueous diluent;
Optionally comprising or consisting of a pH regulator at a concentration of up to 25 mmol / l, preferably 0.1-20 mmol / l; and optionally an osmotic agent at a concentration of up to 200 mmol / l, preferably 20-200 mmol / l Where the aqueous diluent consists of water or a mixture of water and a physiologically acceptable solution, wherein the weight ratio of component (A) to component (B) is from 1: 2 to 1:30, preferably The range is from 1: 3 to 1:30.

  The dosage regimen with which the formulations of the invention can be administered depends on the individual circumstances of each patient and must be carefully considered in each case. Preferably, the recommended dosage regime is 1 mg / kg / day to 10 mg / kg / day, preferably 1.5 mg / kg / day to 3.0 mg / kg / day, based on the weight of the individual patient. The mg amount refers to the amount of component (A).

  Dantrolene or a pharmaceutically acceptable salt thereof is known to reduce excitatory contraction coupling in muscle cells. Accordingly, a further object of the present invention is a pharmaceutical formulation of the present invention for use as a muscle relaxant. Preferably, the pharmaceutical formulation according to the invention is for use in the treatment of diseases associated with muscle spasms, in particular plasticity after stroke. In a particularly preferred embodiment, the pharmaceutical formulation of the present invention is for use in the treatment of malignant hyperthermia.

  In order to treat the disease as effectively as possible, it is important to administer each drug to ensure high target specificity and rapid uptake at the site of action. Accordingly, the pharmaceutical preparations according to the invention are preferably administered parenterally, in particular intravenously.

  A further object of the present invention is a method of treating a pathological condition associated with muscle spasms comprising administering an aqueous composition of the present invention or a pharmaceutical formulation of the present invention. In a preferred embodiment, administration is parenteral, preferably intravenous administration.

  The aqueous compositions and pharmaceutical formulations of the present invention are injectable. This means that aqueous compositions and pharmaceutical formulations are safe for injection.

  “Safe for injection” is defined to mean a formulation that can be reliably injected intravenously at the appropriate clinical dose to the appropriate test subject or model mammal, and the incidence of life-threatening complications from the prescription is In this case, a low incidence means about 10% of cases, preferably less than about 1%. In particular, formulation-related toxicities such as pulmonary embolism (PE) due to ultramicron-sized particles or aggregates, pathologically altered arterial pressure, or severe vascular injury must be limited to a low incidence . In the context of current patents, it is important to point out that the term “safe for injection” does not imply any limitation of drug prescription for intravenous injection, as it allows the formulation to be injected intravenously. It just means that it is safe enough. The reason for focusing on the intravenous route for safety issues is that if the formulation is administered by another injection route such as intramuscular, intraarterial, subcutaneous, intraperitoneal, intraocular or topical infusion, Routes cannot be ignored and often require that the formulation be safe even if the wrong dose is essentially intravenous. For this reason, the terms “safe for intravenous injection” and “all safe for injection” are used interchangeably in this patent.

  Another aspect of the invention focuses on a new indication class for the use of dantrolene or dantrolene salts. In particular, it is an object of the present invention to provide a method for preventing, reducing or reversing the negative cerebrospinal and cognitive damage described herein, which alters blood pressure, particularly reduces blood flow; Cerebral perfusion changes, especially reductions; vascular flow fluctuations, especially reductions, and increased intracranial pressures that alter this impaired cerebral perfusion, and subsequent oxygenation of brain tissue; It may be associated with an abnormal condition, particularly a condition that is maintained for a period of more than about 4 hours. The phenomenon of changes in cognitive ability and function and neuropsychiatric changes with or without impaired motor function are commonly referred to as “pump heads” among anesthesiologists, cardiothoracic surgeons, and other medical personnel. In particular, according to the present invention, one prophylactic administration of dantrolene or a salt, analog or related thereof can be achieved through a unique and synergistic combination of multiple intracellular and / or medullary cells and / or intracellular calcium. It is envisioned that the effects of these neurological complications due to stabilization of can be prevented or limited. Dantrolene is further expected to be an appropriate therapeutic agent that can minimize neurological complications when provided in a timely manner against injury, not only in humans but also in veterinary situations. The

  Furthermore, another aspect of the invention is a novel indication for dantrolene or dantrolene salts, and the existing dantrolene and low volume formulations disclosed herein provide new therapeutic and prophylactic methods. The present inventors have shown that dantrolene or dantrolene salts have unique applicability in the prevention and treatment of certain cerebrospinal injuries and in particular cognitive impairment that have been poorly treated prior to the present invention in biochemical and pharmacological mechanisms. Recognized to provide a surprising and synergistic combination. Paying attention to such injuries, especially when some symptoms are “silent” and sometimes delayed after a certain surgical procedure, has led to a major surgical indication in the previous medical practice. ing.

In addition to what has already been mentioned, the following non-exhaustive list of several advantages of the present invention:
A surprisingly large amount of dantrolene (salt) can be dissolved, in particular a significantly higher concentration of dantrolene (salt) in the solution than was possible with the prior art,
A clear solution that can be easily filtered can be obtained,
A sterile powder formulation is obtained from component (A) a clear filtered liquid solution;
The powder formulation is clear, free of particulate matter and exhibits a rapid reconstitution time resulting in a parenteral solution that is ready for injection;
The preparation reconstituted from the powder formulation meets the regulatory requirements taking into account the regulatory turbidity limits (European Pharmacopoeia sets the limit of turbidity values to NTU = 3);
-A solution of dantrolene (salt) shows very good stability and can be easily injected parenterally,
-This preparation can solubilize a larger amount of dantrolene (salt) in both the initial solution and the reconstitution solution;
When using the preparations (solutions and powders) of the present invention, large amounts of active ingredient can be injected in less time, greatly reducing the time required to reach a therapeutic dose,
-An increase in the bioavailability of dantrolene (salt) is clearly expected.

The invention is illustrated in more detail through the following examples.
Table 1 summarizes the contents of an exemplary composition of the present invention where the aqueous diluent is water and the concentration is based on the total volume of the composition.

  The composition was prepared by dissolving an appropriate amount of dantrolene sodium salt, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and a pH regulator in water and mixing well. The resulting mixture was lyophilized to obtain a dry powder. The powder was then reconstituted in water for injection or an aqueous solution containing 5 wt% dextrose and the pH of the newly obtained solution was determined.

  Experiments were performed using different components (B) and varying the pH of the composition.

  In these experiments, four different cyclodextrins were tested in combination with dantrolene sodium salt. The concentration of the cyclodextrin compound was 50 mg / ml, and the concentration of dantrolene sodium salt was 1 mg / ml. The pH value was adjusted with a buffer consisting of 25 mM phosphate in water and 25 mM tromethamine to reach pH 6.0, 7.0, 8.0, 9.0 and 10.0, respectively. The resulting solution was stored at room temperature and tested for 10 days. The solubility of dantrolene sodium salt was measured after 24 and 48 hours. The solution was analyzed visually, but the content and degradation profile of dantrolene sodium salt was determined by HPLC and pH value monitoring.

  Dantrolene content and degradation profiles were measured on an Agilent Series 1100 HPLC instrument (Agilent Technologies Inc, Santa Clara, CA, USA) equipped with a quaternary pump, autosampler, diode array detector and thermostat column compartment. A Kinex XB-C18 column (75 × 4.6 mm, 2.6 μm, Phenomenex) using a mobile phase consisting of water containing 0.1% formic acid (A) and acetonitrile (B) containing 0.1% formic acid. The use was analyzed by 15% to 45% (B) with a linear gradient of 12 minutes above.

  The pH measurement was performed using a Metrohm pH mobile 826 (Metrohm SA, Herisau, Switzerland) equipped with a glass pH electrode. Measurements were made at 20 ° C. unless otherwise stated.

The following cyclodextrins were tested:
A: Control (phosphate / tromethamine solution)
B: β-cyclodextrin (CAS [7585-39-9])
F: sulfobutylether-β-cyclodextrin sodium salt (degree of substitution 6.0-7.1; CAS [182410-00-0])
D: 2-hydroxyethyl-β-cyclodextrin (molar substitution rate 0.7; CAS [128446-32-2])
E: 2-hydroxypropyl-β-cyclodextrin (molar substitution rate 0.6; CAS [12446-35-5])

  Figures 1-5 are at pH values of 6.0 (Figure 1), 7.0 (Figure 2), 8.0 (Figure 3), 9.0 (Figure 4), and 10.0 (Figure 5). The result of solubility measurement is shown. As can be seen, the solubility was enhanced in all cases and further increased with increasing pH. The best results were obtained when compound (B) was 2-hydropropyl-β-cyclodextrin and almost complete solubility of the dantrolene salt was achieved at pH 9. Improved solubility could be maintained over a long period of time. That is, in the case of the composition according to the present invention, the precipitation of dantrolene sodium usually found in the composition in the art was not observed.

  FIGS. 6-10 show the results of 6.0 (FIG. 6), 7.0 (FIG. 7), 8.0 (FIG. 8), 9.0 (FIG. 8), 9.0 (FIG. 9) and 10.0 (FIG. FIG. 10 shows the degradation profile of dantrolene sodium in the test solution for 10 days at a pH value of FIG. As confirmed by the data, the solution according to the invention is stable even at higher pH values and only slight degradation is observed towards the end of 10 days.

  The improved stability of the composition of the present invention is further demonstrated by the data shown in Table 2. Table 2 shows the effect of 2-hydroxypropyl-β-cyclodextrin on the stability of dantrolene sodium to pH 9 (solution 1) compared to a solution without 2-hydroxypropyl-β-cyclodextrin (solution 3). Show. As can be seen, little loss of dantrolene salt content can be observed (ie, there is little precipitation of dantrolene free acid), while in the absence of 2-hydroxypropyl-β-cyclodextrin. A rapid loss of contents occurred.

The solution was prepared as follows:
Solution 1
10 mg of dantrolene sodium salt was added to 10 ml of 50 mg / ml 2-hydroxypropyl-β-cyclodextrin solution prepared in phosphate / tromethamine buffer (25 mM / 25 mM) adjusted to pH 9 in water. The molar ratio of dantrolene sodium to 2-hydroxypropyl-β-cyclodextrin is about 1:15 (molecular weight: dantrolene sodium M = 399, 33 g / mol and 2-hydroxypropyl-β-cyclodextrin M = 1400 g / mol. Molecular weight). The weight ratio of dantrolene sodium to 2-hydroxypropyl-β-cyclodextrin is 1:50.
Solution 2
Prepared as in Example 1; the weight ratio of dantrolene sodium to 2-hydroxypropyl-β-cyclodextrin is 1:10.
Solution 3-Control solution without cyclodextrin 10 mg of dantrolene sodium salt was added to 10 ml of phosphate / tromethamine buffer (25 mM / 25 mM) adjusted to pH 9.
Solution 4—Comparison Prepared as Solution 1, but used unsubstituted cyclodextrin (ie, β-cyclodextrin).
Solution 5—Comparison Prepared as described in Example 3 of WO2010 / 126818, but with a ratio (w / w) of dantrolene: 2-hydroxypropyl-β-cyclodextrin = 2.5: 1.

  In each case, the solution was filtered and the content of dantrolene sodium salt was measured by HPLC.

  As can be seen from Table 2, the compositions of the present invention exhibit improved stability with respect to the prior art, among others.

  Figures 11 and 12 show the correlation between the solubility of dantrolene sodium salt and the pH of the solution. FIG. 11 shows the data obtained by measuring the solubility of the dantrolene compound after 1 day, while the data summarized in FIG. 12 was obtained after 2 days. As can be seen, the solubility of dantrolene sodium salt increased with increasing pH and the best results were obtained when 2-hydroxypropyl-β-cyclodextrin was also used.

  Furthermore, the powder of the present invention obtained by freeze-drying the solution 2 was compared with the powder of WO2010 / 12681A1. As can be seen from FIG. 13, the preparation of the present invention has a higher amount (+ 100%) of dantrolene sodium compared to the formulation according to WO2010 / 126818A1, due to the specific ratio of component (A) to component (B). Can be solubilized. In fact, much more dantrolene is solubilized in the reconstituted solution, meaning that a greater amount of active ingredient can be injected in a shorter time. In other words, the time required to reach a therapeutic dose is greatly reduced. An increase in bioavailability in the context of this example is also expected. This attribute is more important and critical than ever for patients suffering from malignant hyperthermia due to an emergency. A further difference (not shown in FIG. 13) is that the preparation of the invention is a clear solution, whereas the solution of WO2010 / 126818A1 is not a complete solution but a cloudy heterogeneous mixture. .

  Also, the powder formulation according to the present invention is clear, free of particulate matter, and exhibits a rapid reconstitution time resulting in a parenteral solution that can be injected immediately. Preparations according to WO2010 / 126818A1 are very turbid with particles visible after their reconstitution. The preparation of WO2010 / 126818A1 is 1000 times the turbidity value (milky white) compared to the regulatory limit (NTU = 3) for parenteral products (FIG. 14). Thus, in the present invention, the regulatory limits are met, but not with the preparation according to WO2010 / 126818A1.

  Since the powder according to the invention is derived from a clear and filtered liquid solution of dantrolene sodium, it could be obtained by a sterilization method, whereas the preparation of WO2010 / 126818A1 is a heterogeneous form of suspension formulation It cannot be sterilized by filtration. This is due to the difference in the preparation. According to the invention, component (A) is dissolved (ie a clear solution is obtained), while the preparation of WO2010 / 126818A1 is prepared using a kneading process to obtain a paste.

  In summary, the present invention provides an aqueous dantrolene solution that exhibits not only improved solubility, but also increased stability, particularly in an alkaline environment. It was demonstrated that the best results were obtained with a pH in the range of 8-9, thus avoiding the decomposition of dantrolene salts at higher pH.

Claims (15)

i) a component selected from one or more members of the group consisting of dantrolene and pharmaceutically acceptable salts of dantrolene (A); and ii) a component selected from one or more members of the group consisting of cyclodextrin derivatives (B)
Wherein the pH of the composition is greater than 7 and the molar ratio of component (A) to component (B) ranges from 1: 2 to 1:30 .   The aqueous composition according to claim 1, wherein the molar ratio of component (A) to component (B) ranges from 1: 3 to 1:30, preferably from 1: 5 to 1:18.   The aqueous composition according to claim 1 or 2, wherein the pH of the composition is 7.5 to 10, preferably 8.0 to 9.5, more preferably 8.5 to 9.5.   Component (B) is β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclo Selected from the group consisting of dextrin, 2-hydroxypropyl-γ-cyclodextrin, (2-carboxymethoxy) propyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and 2-hydroxypropyl-β-cyclodextrin The aqueous composition according to any one of claims 1 to 3.   Cyclodextrins in which component (B) has a degree of molar substitution (MS) in the range of 0.05 to 10, preferably 0.2 to 2, in particular 0.25 to 1.0, in particular 0.5 to 0.5. The aqueous composition according to any one of claims 1 to 4, which is a derivative.   The aqueous composition according to any one of claims 1 to 5, further comprising a pH adjusting agent selected from the group consisting of tamin, histidine and mixtures thereof.   The molar ratio of component (A) to pH adjuster is 20: 1 to 1:20, preferably 10: 1 to 1:10, more preferably 8: 1 to 1: 5. Aqueous composition.   The composition is preferably mannitol, fructose, glucose, gluconolactone, gluconate, sucrose, lactose, trehalose, dextrose, dextran, hydroxyethyl starch and mixtures thereof, glycine, gelrantin, calcium gluconoglucoheptanoate, chloride The aqueous composition according to any one of claims 1 to 7, further comprising an osmotic agent selected from the group consisting of potassium, calcium chloride, sodium chloride and mixtures thereof.   A powder obtained by drying the aqueous composition according to one or more of claims 1-8. A kit comprising a) at least one first compartment comprising the powder of claim 9; and b) at least one second compartment comprising an aqueous diluent.   11. Kit according to claim 10, wherein the kit or at least the first and / or at least second compartment is made of a material selected from the group consisting of glass, organic polymer and mixtures thereof. i) dissolving component (A) and component (B) in an aqueous diluent in a molar ratio of 1: 2 to 1:30, preferably 1: 3 to 1:30;
ii) adjusting the pH of the aqueous solution of step a) to greater than 7, preferably in the range of 7.5 to 10   10. A formulation comprising a composition according to one or more of claims 1-8 or a powder according to claim 9 for sampling as a medicament.   14. A formulation according to claim 13 for use as a muscle relaxant.   15. A formulation for use according to one or more of claims 13 or 14, wherein the powder composition is administered parenterally, preferably intravenously.